1. Field of the Invention
The present invention relates to the preparation of a class of 5-heterocyclic substituted tryptamines, e.g., 5-( 1, 2, 4-triazol-1-yl) tryptamine, compounds, therapeutically active as anti-migraine agents. The invention concerns an improved process for producing these 5-heterocyclic substituted tryptamine derivatives which involves a palladium-catalyzed coupling and ting closure.
2. Brief Description of Disclosures in the Art
The complex physiological and pathophysiological processes of the neurotransmitter serotonin (5-HT) are becoming increasingly elucidated..sup.1 (Superscripted References are listed in the back). In one role, serotonin acts as a vasoconstrictor in the brain and, thereby, displays beneficial properties in migraine therapy. Its potential as a pharmaceutical agent, however, is limited due to its rapid metabolism in vivo. Over the past few years an extensive effort has been devoted to the development of N,N-dialkyltryptamines as 5-HT.sub.1D receptor agonists to achieve the desired activity and selectivity for the treatment of migraine. Sumatriptan is the first of this class of drugs to be approved for this purpose..sup.2 MK-0462 (developed by Merck & Co.), is described in U.S. Pat. No. 5,298,520 and is also a potent 5-HT.sub.1D receptor agonist that is undergoing clinical studies. ##STR2##
Generally, this class of compounds is made by the Fisher indole reaction for the preparation of the N,N-dimethyltryptamine framework. Application of this methodology to the synthesis of MK-0462, however, is ineffective and low-yielding due to the instability of the benzyl triazole moiety to the reaction conditions, which generally leads to polymerization of the triazole moiety, producing oligomers. What is desired in the art is a highly efficient method for the preparation of the N,N-dimethyltryptamine, MK-0462 (1) which eliminates the undesirable tendency of triazole polymerization.
Larock et at., have shown that coupling of an iodoaniline species with an internal acetylene using palladium catalysis gives 2,3-disubstituted indoles in good-to-excellent yields..sup.3 Smith et al., have also demonstrated this for 4-pyrimidinyl and pyridinyl derivatives of indol-3-yl-alkyl piperazines as in published EP0 548 831 A1. Two other applications of this methodology have been demonstrated in the syntheses of hetero-condensed pyrroles.sup.4a and tryptophans.sup.4b. However, all of these methods require triphenylphosphine, as part of the catalyst system, which is an environmental hazard.
The application of palladium-catalyzed coupling methodology to the specific synthesis of the 5-triazolyl N,N-dimethyltryptamine ring system, has not been reported previously.